The central objective of the Program Project renewal is to define critical mechanisms mediating neutrophil (PMN) and endothelial activation that induce lung inflammation and vascular injury and lead to protein-rich pulmonary edema and acute lung injury (ALI) and specific mechanisms that lead to recovery. The Program Project is based on the premise that activation of specific signaling pathways in the PMN and the endothelium set into motion events that produce inflammation and, if left unchecked, lead to endothelial injury and tissue edema. In Project 1 Dr. Asrar Malik, P.I., and colleagues will address the concept that cross-talk between PMNs and ECs via NADPH oxidase-derived oxidants is critical in signaling the gating of the novel, oxidant-sensitive transient receptor potential melastatin (TRPM)-2, a Ca++-permeable channel abundant in lung endothelial cells. They will test the postulate that this channel is critical in the mechanism of lung injury. In Project 2 the P.I., Dr. Richard Ye, together with his colleagues, will explore their recent discovery that MAP kinase phosphatase 5 (MKP5) is required for the negative regulation of the phagocyte NADPH oxidase, and thereby modulation of lung injury. This project will test the postulate of this pathway in lung injury. In Project 3 Dr. C. Tiruppathi, P.I. will study the currently uncharacterized but potentially significant role of the transcriptional repressor protein, Dream, as a negative master regulator of the dual function deubiquitinating/E3 ligase enzyme A20, which has a central role in preventing NF-kappaB activation. In Project 4, Dr. Y. Y. Zhao, P.I. will address the role of the Forkhead transcription factor FoxM1 in the repair of endothelial adherens junctions and in the regeneration of the endothelial monolayer after lung vascular injury. We are convinced that a concerted effort as described in this program will lead to a new understanding of the signaling mechanisms responsible for lung inflammatory injury and recovery, which is essential for developing more rational therapeutic strategies based on the underlying pathobiology of lung inflammatory injury and ALI.